The expression "Acquired Immuno-Deficiency Syndrome" (AIDS) was first used in 1981 to describe a state of cellular immune deficiency in homosexuals, characterized by the appearance of opportunistic infections and Kaposi's Sarcoma evolving very aggressively (CDC (Center for Disease Control), MMWR, 30:305-308. DC, (1981)). In 1983 a retrovirus since called HIV (Human Immunodeficiency Virus type 1) was isolated among AIDS patients (Barre-Sinoussi F. et al Science, 220:868-870 (1983)).
Over the past several years, researchers and clinicians have gained considerable experience in studying and caring for individuals infected with HIV throughout the often prolonged course of HIV disease and AIDS. On the basis of this experience, it has become clear that the pathogenic mechanisms underlying HIV infection and disease are not unidimensional, but rather are extremely complex (Fauci A.S., Science, 239, 617, (1988)). Any attempt to design a comprehensive therapeutic strategy for HIV disease must take this fact into account. (Fauci, 1993, Science, 262:1011-1018).
After entry of the HIV virus into cells and uncoating of the HIV particle, reverse transcription of the viral RNA genome into DNA replicas occurs. Among several forms of unintegrated viral DNA (now containing the long repeats [LTRs], at both the 5' and the 3' ends), only the two-LTR linear forms can integrate into the host genome. Such a process appears strictly dependent upon cell activation/replication of T lymphocytes, although "resting" T cells are clearly susceptible to HIV infection. (Zack J. A. et al, Cell; 61, 213-222, (1990)). Furthermore, part of the reverse transcription process also can occur in unactivated T cells, a process that results in the accumulation of incomplete DNA molecules, which may persist for several hours and remain capable of being integrated into the host genome if the cell undergoes sufficient activation (Zack J. A. et al, Cell; 61, 213-222, (1990)). Therefore, infected "resting" CD4.sup.+ T lymphocytes can be considered a transient viral reservoir in infected individuals (Bokrinsky M. I. et al; Science, 254, 423-427, (1991)). These observations are of particular importance in anatomic compartments such as the peripheral blood and lymphoid organs, where the CD4.sup.+ T cell subset represents the predominant infected cell type (Schmittman S. M. et al, Science, 245,305-308, (1989)); (Fox CH. et al J. Infect Dis; 164, 1051-1057, (1991)).
The above discussion provides a sound scientific basis for blocking the initial burst of virus replication and dissemination as well as the persistent replication throughout the course of disease by treating HIV-infected individuals with antiretroviral agents from the earliest time that HIV infection is recognized through the entire course of infection. Unfortunately, currently available agents are only partially effective in suppressing virus replication and spread, and this effect is transient (Hirsch MS, et al, New Engl. J. Med. 328 1686, (1993)). Clear cut, but limited, benefit is seen when 3'-azido-2',3'-didcoxythymidine or azidothymidine (AZT) is given to a patient with advanced HIV disease, and the benefits of early intervention are usually only temporary and do not result in significant long-term advantages with regard to the course of disease and death. (Fauci, 1993, Science, 262:1011-1018).
A number of 2'-3'-dideoxynucleosides have been found to be useful for the treatment or prophylaxis of retroviral infections and especially HIV and AIDS. Examples of such materials include: 2',3'-dideoxy-cytosine (ddC); 2',3'-dideoxyadenosine (ddA); 2',3'-dideoxy-guanosine (ddG); and 2',3'-dideoxy-inosine (ddI) and 2',3' didexoxy-thymidine (d4dT). See European patent application 0206497 and published PCT application number WO 87/01284.
Hydroxycarbamide (HC) was initially synthesized over 120 years ago and has been found to demonstrate activity against a broad spectrum of tumors. (Donehower, Seminars in Oncology, Vol. 19, No. 3, Suppl. 9 (June) 1992: pp 11-19). Additionally, hydroxycarbamide has been used as a viricide. In published PCT application number WO 93/09718, hydroxycarbamide is taught to be useful in a hydrogel polymer coating of a blood bag in order to inhibit viral and HIV infectivity.
Gao et al (PNAS, USA, Vol. 90, pp. 8925-8928, October 1993) disclose that hydroxyurea (hydroxycarbamide) treatment of peripheral blood lymphocytes (PBLs) decreases dNTP levels and the DNA synthesis rate to levels comparable to quicscent PBLs. The article alleges a possible use of hydroxyurea in AIDS therapy.
However, there still remains a need for more effective treatments for the suppression of retroviruses and, in particular, the prevention and/or inhibition of HIV and viral spread. By viral spread, it is intended to include the inhibition of viral replication, and also may include the ability of inhibiting the virus to infect a further host cells.
Objectives of the present invention in the search for new antiretroviral agents include:
1) the identification of compounds with less toxicity and antiviral activity greater than AZT.
2) the development of drug combinations which provide an additive or synergistic effect and decrease the probability of drug resistant isolates.